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Review
, 28 (1), 4-10

Etifoxine for Pain Patients With Anxiety

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Review

Etifoxine for Pain Patients With Anxiety

Yun Mi Choi et al. Korean J Pain.

Abstract

Etifoxine (etafenoxine, Stresam®) is a non-benzodiazepine anxiolytic with an anticonvulsant effect. It was developed in the 1960s for anxiety disorders and is currently being studied for its ability to promote peripheral nerve healing and to treat chemotherapy-induced pain. In addition to being mediated by GABAAα2 receptors like benzodiazepines, etifoxine appears to produce anxiolytic effects directly by binding to β2 or β3 subunits of the GABAA receptor complex. It also modulates GABAA receptors indirectly via stimulation of neurosteroid production after etifoxine binds to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane in the central and peripheral nervous systems, previously known as the peripheral benzodiazepine receptor (PBR). Therefore, the effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine is used for various emotional and bodily reactions followed by anxiety. It is contraindicated in situations such as shock, severely impaired liver or kidney function, and severe respiratory failure. The average dosage is 150 mg per day for no more than 12 weeks. The most common adverse effect is drowsiness at the initial stage. It does not usually cause any withdrawal syndromes. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. It potentiates GABAA receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of TSPO. It seems promising that non-benzodiazepine anxiolytics including etifoxine will replenish shortcomings of benzodiazepines and selective serotonin reuptake inhibitors according to animated studies related to TSPO.

Keywords: Antianxiety drugs; Anticonvulsants; Anxiety; Etifoxine; Gamma-aminobutyric (GABA) receptors; Human translocator protein (18kDa); Mechanism of action; Nerve regeneration; Neuropathic pain; Neurosteroids.

Figures

Fig. 1
Fig. 1
Schematic action mechanism of etifoxine (EFX). Hypothetical schematic model of the GABAA receptor is a pentameric structure, with the five subunits (two α, two β, and a single γ subunit) arranged around a central chloride-selective pore. A variety of chemical compounds are capable of acting on GABAA receptors to modulate its channel function. The receptor has specific sites for each chemical compound (benzodiazepines, barbiturates, and neurosteroids), which are allosteric sites for modulation of GABA currents or chloride conductance. Etifoxine is a direct potentiation of GABAA receptor activation though a site different from the classical benzodiazepine binding motif. (A) Presumably etifoxine appears to produce its anxiolytic effects by binding to β2 and β3 subunits of the GABAA receptor complex. The effects of etifoxine are not reversed by the benzodiazepine antagonist flumazenil. (B) In addition, etifoxine modulates GABAA receptors via stimulation of neurosteroid production. This occurs through the binding of etifoxine to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane, known as the peripheral benzodiazepine receptor (PBR). TSPO or PBR interacts with a voltage-dependent anion channel (VDAC, a protein that is present in outer mitochondrial membrane - inner mitochondrial membrane contact sites) and the adenine nucleotide transporter (ANT, in inner mitochondrial membrane) to form a complex. Cholesterol transport across the outer mitochondrial membrane through TSPO is activated by etifoxine binding to the protein. The cholesterol side-chain-cleaving cytochrome P450 enzyme (P450scc), which is located at the inner mitochondrial membrane, converts cholesterol to pregnenolone, which is further metabolized through several steps by enzymes present in the endoplasmic reticulum and finally converted into neurosteroid allopregnanolone (ALLO). ALLO acts in an autocrine and paracrine manner and are potent positive allosteric modulators of synaptic and extrasynaptic GABAA receptor. They also modulate GABAA receptor function through a binding site different from that of benzodiazepines (adapted from Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 2010; 9: 971-88).

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References

    1. Means-Christensen AJ, Roy-Byrne PP, Sherbourne CD, Craske MG, Stein MB. Relationships among pain, anxiety, and depression in primary care. Depress Anxiety. 2008;25:593–600. - PubMed
    1. Farb DH, Ratner MH. Targeting the modulation of neural circuitry for the treatment of anxiety disorders. Pharmacol Rev. 2014;66:1002–1032. - PubMed
    1. Almeida TF, Roizenblatt S, Tufik S. Afferent pain pathways: a neuroanatomical review. Brain Res. 2004;1000:40–56. - PubMed
    1. Willis WD, Westlund KN. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol. 1997;14:2–31. - PubMed
    1. Price DD. Central neural mechanisms that interrelate sensory and affective dimensions of pain. Mol Interv. 2002;2:392–403. 339. - PubMed

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